KR19980703434A - Gelatin capsules with controlled water activity - Google Patents

Abstract

A gelatin capsule having adjusted water activity and preserved in a closed system, which contains, packed therein, an additive(s) selected from carboxymethyl cellulose calcium, crosscarmellose sodium, partially gelatinized starch and polyvinyl polypyrrolidone in the proportion of 50 to 150 wt. % of the total quantity of the gelatin of the said capsule.

Description

Gelatin capsules with controlled water activity

The quality of the capsule, ie the stability of its structure, the pharmacological activity of the drug as its contents and its appearance are closely related to water activity. For example, even if gelatin capsules are made under suitable conditions, the moisture and solvent in the capsule coat evaporate, especially during storage in a closed system under heating, which results in a high moisture content (high water activity) inside the capsule. . If the drug contains an active ingredient that is prone to change with moisture, or if the moisture cannot be easily separated from the active ingredient and there are impurities unstable in the moisture, the drug is essentially in contact with the free water present in the capsule. As a result, it may become unstable over time. This may result in a decrease in the activity of the active ingredient as well as in appearance changes such as coloring. In addition, the gelatin capsules themselves may be insoluble and softened, resulting in deformation or similar phenomena. In general, control of water activity, in particular reduction of water activity, was carried out by placing a desiccant, such as silica gel, in a container for packaging the capsule to reduce the internal moisture of the capsule. However, it is not easy to properly control the water content in the capsule coating by this method. In particular, in the case of gelatin capsules, if the water content is reduced too much, cracks or crack breakage may occur and the capsules may be damaged or deformed. Normal moisture content or moisture content of the gelatin capsule coating is 12 to 16%, and when the water content or moisture content is less than 10%, in particular less than 7 to 8%, cracking may occur even with a slight impact. Therefore, it is desirable to reduce the free water content inside the capsule while properly maintaining the moisture content in the gelatin coating. However, the manufacture of such capsules is difficult.

Stabilized gelatin capsules have been reported in, for example, Japanese Patent Application Laid-Open No. 80,930 / 1991, Japanese Patent Application Laid-Open No. 145,017 / 1992 and Japanese Patent Publication No. 159,218 / 1992. However, these publications all relate to gelatin capsules containing a stabilizer in the gelatin coating, and do not mention any control of water activity inside the capsule. Therefore, these documents do not solve the above problems. Japanese Unexamined Patent Publication No. 24,014 / 1978 reports gelatin capsules containing polyvinyl pyrrolidone. However, the amount of polyvinyl pyrrolidone used per capsule is very small and its purpose is to control the release rate of the drug.

Under the above conditions, the inventors of the present invention have intensively studied to establish a method for appropriately adjusting the water activity inside the capsule (ie, the inside water activity of the capsule) and developing a capsule in which the water activity is controlled.

As a result, the present invention has been established on the basis of the fact that it is useful to add a specific substance which acts as a water activity regulator to the capsule contents in order to appropriately regulate the internal water activity of the capsule without adversely affecting the gelatin coating.

Summary of the Invention

In the present invention, an additive selected from the group consisting of carboxymethylcellulose calcium, croscarmellose sodium, partially gelatinized starch and polyvinyl polypyrrolidone is filled into the gelatin capsule at a ratio of 50 to 150% by weight relative to the total weight of the gelatin of the gelatin capsule. The present invention provides a gelatin capsule, which regulates water activity and is preserved in a closed system.

The present invention relates to a gelatin capsule having improved internal moisture stability in a closed system by controlling the water activity of the contents of the gelatin capsule.

1 is a graph showing the relationship between the temperature and water activity of gelatin preserved in a closed system.

2 contains only aspirin or additives [CS (corn starch); MCC (crystalline cellulose); CMS (carboxymethyl cellulose Ca); PCS (Partially Gelatinized Starch)] is a graph showing the stability of aspirin in capsules when stored in a closed system while heating at 60 ° C.

3 shows the addition ratio of the additives to gelatin, gelatin beads and additives [PVPP (polyvinyl polypyrrolidone); Ac-di-Sol; CMC-Ca; PCS] is a graph showing the relationship between the water activity of gelatin beads in a mixture containing various mixing ratios and stored in a closed system (25 ° C).

FIG. 4 is a graph showing the relationship between the ratio of additives to gelatin and the water activity of gelatin beads in a mixture stored in a heated (45 ° C.) hermetic system similar to that used in FIG. 3.

FIG. 5 is a graph showing the relationship between the ratio of additives to gelatin and the water activity of gelatin beads in a mixture stored in a heated (60 ° C.) hermetic system similar to that used in FIG. 3.

The coating of the gelatin capsule of the present invention preferably contains gelatin as a main component, and optionally contains a small amount of an additive for capsule coating (for example, polyethylene glycol, etc.) commonly used in the pharmaceutical industry.

For the purposes of the present invention, the selected additive acts as a water activity regulator (or modulator) as mentioned above and is about 50 to 150% by weight, preferably about 50 to 120% by weight, more of the total weight of the gelatin coating in the capsule. It is preferably filled at a rate of about 50 to 100% by weight, more preferably about 70 to 100% by weight, particularly preferably about 75 to 90% by weight.

If the amount of the additive is too small, the internal water activity cannot be effectively controlled when the capsule is stored under high temperature and high humidity or for a long time, which may cause destabilization or discoloration of the capsule or its contents. If the amount of the additive is too large, the internal water activity can be greatly reduced under mild conditions of room temperature, and cracking may occur in the gelatin capsule.

Throughout this specification, the term water activity (A _W ) refers to the ratio of the water vapor pressure (P) in a particular measurement system to the water vapor pressure (Po) of pure water under the same temperature and pressure as that of the measurement system, wherein the formula A _W = ( P / Po) × 100 (%).

The water activity of gelatin, additives and whole capsules can be determined by any one of the commercially available measuring devices, such as Rotronic, Inc. (Guns Industrial Co., Gunze Industrial Co., Ltd.). Ltd.)) can be used using a DT type water activity (A _W ) measuring system.

The total water activity (A _WT ) of the capsule is, in principle, equal to the average water activity ( A _W ) which can be calculated from the water activity of each of the gelatin and the additive as the main components of the capsule coating, filled in the capsule according to Equation 1 below. However, they differ from one another when the transfer of moisture occurs between the coating and the additive due to the filling of the additive in the capsule.

A _W = [A _W · M (Gelatin) + A _W · M (Additive)] / [M (Gelatin) + M (Additive)]

Where

A _W is the average water activity,

A _W is individual water activity,

M is the individual moisture content.

Throughout this specification, when discussing the change in water activity with respect to the water stability of the capsule, the average water activity ( A _W ) calculated according to Equation 1 based on the individual water activity before filling the additive, and The difference in the A _WT values of the capsules calculated after filling the additive is more important than the change in absolute water activity measured for each of the gelatin and the additive. I.e., from the capsular A _W larger the value obtained by subtracting the A _WT, the water additive to move to the capsule shell from the more often, which means an increase in the water activity in the capsules is suppressed. Capsules of the present invention may contain any pharmacologically active and pharmaceutically acceptable agent, provided that they do not adversely interact with the additive. However, materials that are susceptible to changes in pharmacological activity and biochemical properties (eg color, particle size, etc.) due to changes in water activity, especially increased water activity, are suitable. Examples of such substances include antibiotics (eg 7β-[(Z) -2- (2-amino-4-thiazolyl) -2-hydroxyiminoacetamide]-(1,2,3-triazole -4-ylthimethylthio) -1-carba-3-cefe-4-carboxylic acid) and aspirin. Incidentally, in some cases the biochemical changes of these agents are due to the contaminants accompanying the active ingredient as well as the active ingredient.

Gelatin capsules obtained according to the method of the present invention are unexpectedly stable when the gelatin capsules are generally stored in an unstable closed system. In particular, inotropic medications that are otherwise adversely affected by high water activity can be stably maintained in gelatin capsules even in closed systems at elevated temperatures. At the same time, the gelatin capsule film itself was also stabilized. Therefore, the present invention can contribute to the maintenance of the quality of the capsule which is considered to be easily degraded during transportation or storage.

Throughout this specification, the term closed system is a system that is completely blocked to allow the dispersion of outside air, and is preferably packaged in a press-through package (PTP), alumin-pillow, or the like. It means.

Capsules of the present invention can be prepared in a conventional manner using conventional carriers, excipients and the like, except for including an appropriate amount of additives which act as water activity regulators. However, experiments have shown that additives such as corn starch, crystalline cellulose, lactose, mannitol, sucrose, etc., which are commonly formulated in standard capsules, have been found to adversely affect the decrease in water activity (see Example 2 below). When using these additives in the preparation of the capsules of the present invention, it may be desirable to appropriately control their content. For example, relatively small amounts of lactose-like materials are useful as excipients when preparing the capsules of the present invention under conditions that do not adversely affect the decrease in water activity.

The present invention will now be described in more detail in the following examples. However, these are only examples and should not be taken as limiting the scope of the present invention.

In the following examples, the water content and water activity of the coating and the contents of the capsules were measured under the following conditions.

Water activity :

Apparatus: DT type water activity (A _W ) measuring system manufactured by Rotronics & Co., Ltd. (Guns Industrial Co., Ltd.);

Test piece: 3 g; And

Temperature of jacket: 25 ± 2 ° C .; 45 ± 2 ° C .; Or 60 ± 2 ° C.

Water content :

Thermostat: SATAKE vacuum thermostat;

Temperature: 60 ± 1 ° C .;

Vacuum degree: 5 mmHg or less (phosphorus pentoxide);

Drying time: 4 hours; And

Test piece: 0.5-1.0 g (container: 1.7 cm in diameter, thickness of the test piece: about 7 mm).

The measured moisture content was expressed as the ratio (%) of the weight loss amount (dry weight) to the dry weight of the test piece.

Test Example 1 Effect of temperature on the water activity of gelatin

The water activity of the gelatin to be used in the capsule coating was evaluated in a closed system under the conditions described above. The result obtained using only gelatin is shown in FIG.

From FIG. 1, it can be seen that the water activity of the gelatin increases with increasing temperature (ie, 45% at 40 ° C .; 55% at 50 ° C .; and 70% at 60 ° C.). From these results, it can be seen that when heated under sealed conditions, water evaporates from the gelatin coating of the capsule, thereby making the state inside the capsule high humidity (high water activity).

Test Example 2 Selection of additives showing a decrease in water activity in the presence of gelatin

Selection of materials suitable for reducing the water activity inside the gelatin capsule was carried out by keeping various additives alone or in a 1: 1 mixture with gelatin (beads) in a closed system and determining the water activity and water content. In particular, 1.5 g of the additive, or a mixture of 1.5 g of the additive and 1.5 g of gelatin beads, were placed in a vial, sealed with a stopper, and held at a constant temperature (25 ° C., 45 ° C. or 60 ° C.) for 14 days. Then, the water activity and water content of the individual additives and gelatin were measured. The water activity of the additive preserved in the presence of gelatin beads was measured by a device for measuring the water activity adjusted at the same temperature as when stored. The water content of each additive after storage was measured under the conditions after removing gelatin beads from the mixture. The results are shown in Table 1 below.

Water activity Additive (alone) (A _W ) Additive + Gelatin (A _WT ) 25 ℃ 45 ℃ 60 ℃ 45 ℃ 60 ℃ Lactose 38.6 31.6 32.3 57.0 (57.8) 68.5 (68.3) Per powder 11.4 22.4 26.8 57.4 (59.2) 67.8 (70.4) Mannitol 35.4 24.1 23.1 57.8 (59.2) 67.2 (70.2) Corn starch 41.2 61.2 73.4 67.4 (60.2) 78.6 (71.8) Crystalline cellulose 36.9 54.2 63.3 56.1 (58.0) 67.4 (68.5) L-HPLC 15.1 30.0 38.2 45.4 (51.9) 56.3 (62.2) Gelatin (alone) 39.2 59.3 70.3 - - PVPP 6.1 20.0 26.6 34.3 (49.0) 46.9 (58.9) Ac-Di-Sol 3.8 13.3 21.0 30.1 (52.2) 41.1 (62.7) CMC-Ca 2.2 11.4 20.0 30.9 (54.8) 42.6 (60.2) PCS 16.0 32.4 39.1 44.4 (54.8) 56.8 (65.1) Note: Numbers in parentheses represent the average water activity ( A _W ) calculated from measurements of gelatin and individual additives.

Water content Additive (alone) Additive + Gelatin 25 ℃ 45 ℃ 60 ℃ Lactose 0.74 0.69 0.50 Per powder 0.02 0.02 0.04 Mannitol 0.04 0.05 0.05 Corn starch 12.06 11.93 11.44 Crystalline cellulose 4.36 4.31 4.31 L-HPLC 4.38 5.69 5.86 Gelatin (alone) 13.0 - - PVPP 4.61 6.83 6.81 Ac-Di-Sol 2.37 5.38 5.61 CMC-Ca 3.26 6.24 6.68 PCS 2.58 7.95 8.04 Note: Preservation conditions: sealed in vials for 14 days at 25 ° C., 45 ° C. or 60 ° C. (gelatin 1.5 g + additive). L-HPC: Less substituted hydroxypropyl cellulose PVPP: Polyvinyl polypyrrolidone Ac-Di-Sol (Asahi Kasei / FMC Corporation) CMC-Ca: carboxymethyl cellulose calcium PCS: partially gelatinized starch

Table 1 shows that polyvinyl polypyrrolidone (PVPP), croscarmellose sodium (Ac-Di-Sol), carboxymethyl cellulose calcium (CMC-Ca) and partially gelatinized starch (PCS) are useful for reducing water activity inside capsules. Indicates.

Table 1 also indicates that corn starch and crystalline cellulose, which are often used in the standard formulation of capsules, adversely affect the reduction in water activity, from which caution is used when using these additives in formulations containing agents affected by moisture. I can see.

Test Example 3 Stability of Aspirin in Capsules Stored in a Closed System Under Heating

Fill a hard gelatin capsule (No. 4) with a powder mixture (160 mg) (1: 1) of aspirin (AS) and additives, and heat at 60 ° C. while keeping the capsule in a closed system defined by the use of BVK14 vials, The test was performed by measuring the aspirin content over time. The result is shown in FIG.

From Fig. 2 it is clear that aspirin is noticeably degraded when stored alone. However, degradation of aspirin is inhibited in the presence of partially gelatinized starch (PCS) or carboxymethyl cellulose calcium (CMC), but promoted in the presence of corn starch (CS) or crystalline cellulose (MCC).

Test Example 4 Chemical Stability of Aspirin Capsules Containing Various Ratios of Additives

Gelatin capsules containing aspirin (AS) at a ratio of 1.5 to gelatin as a model medicament can be added to the gelatin capsules at various mixing ratios ((r) = 0.2, 0.5, 1.0, 1.5) to gelatin (PCPP, Ac-Di-Sol, Prepared in the absence or presence of CMC-Ca, PCS). The capsules are then subjected to an accelerated test (3 months at 45 ° C.) or to a harsh test (2 weeks at 60 ° C.) corresponding to a normal time-test (2 years at room temperature) and to aspirin remaining in the capsule containing aspirin Rate (%) and water activity (A _WT ) were measured. The results are shown in Table 2 below.

Weight ratio Survival rate (%) Water activity (%) 45 ℃, 3 months 60 ℃, 2 weeks AS / Gelatin Capsule (GEL-Cap) (1.5) /1.0 84.1 (63.9) 77.2 (75.7) AS + PVPP / GEL-Cap (1.5, 0.2) /1.0 93.3 (48.0) 83.6 (64.0) (1.5, 0.5) /1.0 98.0 (42.0) 90.3 (56.2) (1.5, 1.0) /1.0 99.8 (35.2) 92.8 (48.0) (1.5, 1.5) /1.0 100.0 (31.2) 98.0 (44.0) AS + Ac-Di-Sol / GEL-Cap (1.5, 0.2) /1.0 93.8 (46.4) 85.5 (60.9) (1.5, 0.5) /1.0 100.0 (37.8) 90.2 (53.6) (1.5, 1.0) /1.0 100.0 (30.6) 97.0 (43.2) (1.5, 1.5) /1.0 100.0 (25.4) 99.9 (36.8) AS + CMC-Ca / GEL-Cap (1.5, 0.2) /1.0 94.2 (46.5) 85.4 (62.1) (1.5, 0.5) /1.0 100.0 (37.8) 92.1 (53.6) (1.5, 1.0) /1.0 100.0 (32.0) 99.3 (44.5) (1.5, 1.5) /1.0 100.0 (26.2) 100.0 (36.9) AS + PCS / GEL-Cap (1.5, 0.2) /1.0 95.2 (49.1) 83.6 (66.8) (1.5, 0.5) /1.0 100.0 (39.8) 92.8 (58.4) (1.5, 1.0) /1.0 100.0 (39.8) 99.8 (52.2) (1.5, 1.5) /1.0 100.0 (36.0) 100.0 (48.3)

From Table 2, for the accelerated test (45 ° C., 3 months), the aspirin content is reduced by about 84% in the absence of additives, but the decrease in aspirin content is any of the four additives at a rate of at least about 50% by weight of the gelatinous coating. It was almost suppressed by filling one. In addition, in the case of a severe test for two weeks at 60 ° C., aspirin residual ratio of 90% or more can be obtained by filling the capsule with an additive at a ratio of about 50% or more of the gelatin coating.

Test Example 5 Effect of Mixing Ratio of Additives to Gelatin on Water Activity

Additives (PVPP, Ac-Di-Sol, CMC-Ca or PCS) found to be effective in reducing water activity in Test Example 2 were mixed with gelatin beads at a given mixing ratio (r), and 1.5 g of gelatin beads and additives ( A mixture containing 1.5 × (r)) g, wherein (r) is 0, 0.2, 0.5, 1.0, 1.5, was obtained. The resulting mixture was then stored in sealed vials for 14 days under heating (25 ° C., 45 ° C. or 60 ° C.) and then water activity was measured in the same manner as described in Test Example 2. The results obtained after storage at 25 ° C., 45 ° C. and 60 ° C. are provided in FIGS. 3, 4 and 5, respectively. 3 to 5 are additives that can reduce the water activity can reduce the water activity of the entire system under any temperature conditions according to the amount of use, the water activity of the system as the temperature increases regardless of the type of additive Increase. In the figures, a is No. 1 containing 4.6% PEG (polyethylene glycol) (cap body OP. White, Eranco, Japan). 4 Shows the water activity which may cause cracks in the capsule film. If the water activity decreases below the value in a, the plasticity of the capsule coating decreases, increasing the likelihood of cracking due to breakage during transportation or storage. As can be seen in FIG. 3, the preferred mixing ratio of the additive to the capsule coating is 150% or less at a storage temperature of 25 ° C.

Example 1

Capsules were made with the following ingredients.

aspirin 112.4 mg CMC-Ca 35.0 mg Carplex 67 (Sionogi) 1.7mg Magnesium stearate 1.7mg 150.8 mg

The above ingredients were mixed and the powder mixture was No. 4 size hard gelatine capsules (40 mg) were filled to obtain a capsule (190.8 mg).

Example 2

Capsules were made with the following ingredients.

aspirin 112.4 mg CMC-Ca 30.0 mg Carplex 67 (Sionogi) 1.5mg Magnesium stearate 1.5mg Lactose 9.6mg 155.0mg

The above ingredients were mixed and the powder mixture was No. 4 size hard gelatine capsules (40 mg) were filled to obtain a capsule (195.0 mg).

Example 3

Capsules were made with the following ingredients.

aspirin 107.0mg Ac-Di-Sol 40.0mg Carplex 67 (Sionogi) 1.0mg Magnesium stearate 2.0mg Lactose 5.0mg 155.0mg

The above ingredients were mixed and the powder mixture was No. 4 size hard gelatine capsules (40 mg) were filled to obtain a capsule (195.0 mg).

Example 4

Capsules were made with the following ingredients.

aspirin 102.0mg PVPP 48.0 mg Carplex 67 (Sionogi) 1.0mg Magnesium stearate 2.0mg Lactose 2.0mg 155.0mg

The above ingredients were mixed and the powder mixture was No. 4 size hard gelatine capsules (40 mg) were filled to obtain a capsule (195.0 mg).

As can be seen from the results shown in the test examples, the gelatin capsule of the present invention properly maintains water activity even in a closed system under heating. Accordingly, the present invention provides a gelatin capsule that not only is stable but also contributes to maintaining the quality of the capsule by keeping the contents containing the medicament susceptible to moisture for a long time.

Claims (5)

In a gelatin capsule preserved in an airtight system, an additive selected from the group consisting of carboxymethyl cellulose calcium, croscarmellose sodium, partially gelatinized starch and polyvinyl polypyrrolidone is 50 to 150% by weight based on the total weight of the gelatin of the capsule. A gelatin capsule with controlled water activity, which is filled in a gelatin capsule at a ratio of. The method of claim 1, Gelatin capsules of the additive amount of 50 to 120% by weight relative to the total weight of gelatin. The method according to claim 1 or 2, A gelatin capsule wherein the additive is carboxymethyl cellulose calcium. The method according to any one of claims 1 to 3, Gelatin capsules packaged in a press-through package. A method of stabilizing gelatin capsules, characterized by using an additive selected from the group consisting of carboxymethyl cellulose calcium, croscarmellose sodium, partially gelatinized starch and polyvinyl polypyrrolidone as a water activity regulator.